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1.
Lancet Diabetes Endocrinol ; 8(11): 880-893, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32971040

RESUMO

BACKGROUND: Patients with type 2 diabetes have a high risk of developing chronic kidney disease. We examined the effects of semaglutide on kidney function and safety in a large, broad type 2 diabetes population. METHODS: We did a post-hoc analysis of 8416 patients with type 2 diabetes enrolled in the SUSTAIN 1-5 and SUSTAIN 7 randomised controlled trials, and the SUSTAIN 6 cardiovascular outcomes trial, to examine the effects of once-weekly subcutaneous semaglutide 0·5 mg and 1·0 mg versus comparators (active treatments or placebo) on estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and kidney adverse events. Data from SUSTAIN 1-5 and SUSTAIN 7 were pooled. eGFR and UACR were also analysed by kidney function and albuminuria status. FINDINGS: In SUSTAIN 1-5 and SUSTAIN 7, eGFR decreased from baseline to week 12 with all active treatments; estimated treatment differences (ETDs) versus placebo were -2·15 (95% CI -3·47 to -0·83) mL/min per 1·73 m2 with semaglutide 0·5 mg and -3·00 (-4·31 to -1·68) mL/min per 1·73 m2 with semaglutide 1·0 mg; after week 12, eGFR plateaued. In SUSTAIN 1-5 and SUSTAIN 7, from baseline to end of treatment the decline in eGFR was greater with semaglutide than with placebo (ETD -1·58 [95% CI -2·92 to -0·25] mL/min per 1·73 m2 with semaglutide 0·5 mg and -2·02 [-3·35 to -0·68] mL/min per 1·73 m2 with semaglutide 1·0 mg). In SUSTAIN 6, the decline in eGFR was greater with semaglutide than with placebo from baseline to week 16 (ETD -1·29 [95% CI -2·07 to -0·51] mL/min per 1·73 m2 with semaglutide 0·5 mg and -1·56 [-2·33 to -0·78] mL/min per 1·73 m2 with semaglutide 1·0 mg), but not from week 16 to week 104 (1·29 [0·30 to 2·28] mL/min per 1·73 m2 with semaglutide 0·5 mg and 2·44 [1·45 to 3·44] mL/min per 1·73 m2 with semaglutide 1·0 mg). Overall (ie, from baseline to week 104), the eGFR decline in SUSTAIN 6 was similar between semaglutide and placebo (ETD 0·07 [95% CI -0·92 to 1·07] mL/min per 1·73 m2 with semaglutide 0·5 mg and 0·97 [-0·03 to 1·97] mL/min per 1·73 m2 with semaglutide 1·0 mg). In SUSTAIN 1-5, UACR ratios at end of treatment to baseline were 0·917 with semaglutide 0·5 mg, 0·836 with semaglutide 1·0 mg, and 1·239 with placebo; at end of treatment, greater reductions in UACR were observed with semaglutide versus placebo (estimated treatment ratios 0·74 [95% CI 0·64 to 0·85] for semaglutide 0·5 mg and 0·68 [0·59 to 0·78] for semaglutide 1·0 mg). In SUSTAIN 6, UACR ratios at end of treatment (week 104) to baseline were 0·973 with semaglutide 0·5 mg, 0·858 with semaglutide 1·0 mg, and 1·302 with placebo; at week 104, greater reductions in UACR were observed with semaglutide versus placebo (estimated treatment ratios 0·75 [95% CI 0·66 to 0·85] for semaglutide 0·5 mg and 0·66 [0·58 to 0·75] for semaglutide 1·0 mg). In SUSTAIN 1-7, eGFR initially declined in patients with normal kidney function (and in those with mild kidney impairment with semaglutide 1·0 mg in SUSTAIN 6), but overall (ie, by week 30 for SUSTAIN 1-5 and SUSTAIN 7, and week 104 for SUSTAIN 6), eGFR did not differ between semaglutide and placebo. In SUSTAIN 1-6, UACR decreased in patients with pre-existing microalbuminuria or macroalbuminuria at baseline; it did not change or increased in those with normoalbuminuria at baseline. Kidney adverse events were balanced between treatment groups. INTERPRETATION: Across the SUSTAIN 1-7 trials, semaglutide was associated with initial reductions in eGFR that plateaued, and marked reductions in UACR. This post-hoc analysis suggests no increase in the risk of kidney adverse events with semaglutide versus the active comparators used across SUSTAIN 1-7. FUNDING: Novo Nordisk.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Taxa de Filtração Glomerular/efeitos dos fármacos , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Rim/efeitos dos fármacos , Adulto , Idoso , Diabetes Mellitus Tipo 2/urina , Esquema de Medicação , Feminino , Taxa de Filtração Glomerular/fisiologia , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Humanos , Injeções Subcutâneas , Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
2.
Am Heart J ; 229: 61-69, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32916609

RESUMO

Cardiovascular disease (CVD) is a major cause of morbidity and mortality. Although it has been widely appreciated that obesity is a major risk factor for CVD, treatments that produce effective, durable weight loss and the impact of weight reduction in reducing cardiovascular risk have been elusive. Instead, progress in CVD risk reduction has been achieved through medications indicated for controlling lipids, hyperglycemia, blood pressure, heart failure, inflammation, and/or thrombosis. Obesity has been implicated as promoting all these issues, suggesting that sustained, effective weight loss may have independent cardiovascular benefit. GLP-1 receptor agonists (RAs) reduce weight, improve glycemia, decrease cardiovascular events in those with diabetes, and may have additional cardioprotective effects. The GLP-1 RA semaglutide is in phase 3 studies as a medication for obesity treatment at a dose of 2.4 mg subcutaneously (s.c.) once weekly. Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) is a randomized, double-blind, parallel-group trial testing if semaglutide 2.4 mg subcutaneously once weekly is superior to placebo when added to standard of care for preventing major adverse cardiovascular events in patients with established CVD and overweight or obesity but without diabetes. SELECT is the first cardiovascular outcomes trial to evaluate superiority in major adverse cardiovascular events reduction for an antiobesity medication in such a population. As such, SELECT has the potential for advancing new approaches to CVD risk reduction while targeting obesity.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Peptídeos Semelhantes ao Glucagon , Obesidade , Sobrepeso , Perda de Peso/efeitos dos fármacos , Cardiotônicos/administração & dosagem , Cardiotônicos/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Feminino , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Avaliação de Resultados em Cuidados de Saúde , Sobrepeso/diagnóstico , Sobrepeso/tratamento farmacológico , Sobrepeso/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
Postgrad Med ; 132(sup2): 15-25, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32815436

RESUMO

Oral semaglutide is a tablet formulation of a glucagon-like peptide-1 receptor agonist (GLP-1RA), recently approved in the USA and other countries. This paper reviews data from clinical trials (PIONEER 1, 2, 3, and 7) comparing oral semaglutide (once-daily doses of 3, 7, or 14 mg) with either once-daily placebo, empagliflozin 25 mg, or sitagliptin 100 mg. After 26 weeks in PIONEER 1, patients randomized to 3, 7, or 14 mg doses of oral semaglutide monotherapy had statistically significant reductions in glycated hemoglobin (HbA1 c) of 0.9%, 1.2%, and 1.4%, respectively, versus 0.3% with placebo. In the active-comparator studies, oral semaglutide 14 mg provided better glycemic control than empagliflozin or sitagliptin after 26 weeks, with durable effects. Body weight reductions were significantly greater with oral semaglutide than with placebo and sitagliptin. However, body weight reductions with oral semaglutide 14 mg versus empagliflozin 25 mg were not significantly different. Gastrointestinal adverse events (AEs) with oral semaglutide were mostly mild-to-moderate, occurred early in the course of treatment, and abated over time. Across these trials, 5-13% and 15-20% of patients experienced nausea with oral semaglutide 7 and 14 mg, respectively, and 2.3-3.4% and 5.1-8.0%, respectively, discontinued treatment due to gastrointestinal AEs. Severe or blood glucose-confirmed symptomatic hypoglycemia occurred infrequently with oral semaglutide and was seen most often in patients taking concomitant sulfonylureas. Findings from these trials indicate that the addition of oral semaglutide reduces HbA1 c and body weight and is associated with a low risk of hypoglycemia. Oral semaglutide represents an additional option for treating people with type 2 diabetes in primary care, with the potential to expand the numbers of patients benefiting from GLP-1RAs beyond that currently seen with injectable formulations.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Hipoglicemiantes/administração & dosagem , Administração Oral , Compostos Benzidrílicos/administração & dosagem , Ensaios Clínicos como Assunto , Glucosídeos/administração & dosagem , Hemoglobina A Glicada/efeitos dos fármacos , Humanos , Atenção Primária à Saúde , Fosfato de Sitagliptina/administração & dosagem
4.
Postgrad Med ; 132(sup2): 26-36, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32815423

RESUMO

Injectable therapies such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and insulin are high-efficacy options for people with type 2 diabetes (T2D) who require treatment intensification. In addition to high glycemic efficacy, GLP-1RAs offer weight loss benefits, and some agents have been shown to reduce cardiovascular risk. This article summarizes data from two clinical studies with the first oral GLP-1RA, oral semaglutide, in situations where injectable therapy is often considered, and provides guidance on use in primary care. PIONEER 4 compared oral semaglutide 14 mg with an injectable GLP-1RA, liraglutide 1.8 mg, or placebo in patients uncontrolled on oral glucose-lowering therapies. PIONEER 8 compared oral semaglutide with placebo in patients with T2D already on insulin therapy. Treatment with oral semaglutide gave similar reductions in glycated hemoglobin (HbA1 c) compared with liraglutide at 26 weeks, and significantly greater reductions at 52 weeks. Changes in body weight with oral semaglutide were significantly greater compared with liraglutide after 26 and 52 weeks. Adding oral semaglutide 7 or 14 mg to insulin resulted in significant reductions in HbA1 c and body weight at both 26 and 52 weeks compared with placebo, and facilitated a decrease in total daily insulin dosage. Oral semaglutide was associated with low proportions of patients experiencing severe or blood glucose-confirmed symptomatic hypoglycemia when added to oral glucose-lowering therapies, and did not increase the incidence of such events when added to insulin. The tolerability profile of oral semaglutide was consistent with that seen for injectable GLP-1RAs, with gastrointestinal side effects seen most frequently; most were transient and tended to occur during dose escalation. For patients requiring treatment intensification after oral therapy or as add-on to insulin, oral semaglutide provides effective glucose lowering and body weight loss, with low risk of hypoglycemia, thus broadening the range of therapeutic options for treatment of T2D in primary care.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Hipoglicemiantes/administração & dosagem , Administração Oral , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Insulina/uso terapêutico , Placebos , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
Postgrad Med ; 132(sup2): 37-47, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32815439

RESUMO

Patients with type 2 diabetes (T2D) often have comorbidities, such as cardiovascular disease or chronic kidney disease, and a large and growing proportion of the T2D patient population is over 65 years. There are many therapies for the treatment of T2D but not all are suitable for patients with comorbidities. Oral semaglutide is a tablet formulation of a glucagon-like peptide-1 receptor agonist (GLP-1RA) and was recently approved for the treatment of T2D, representing an oral alternative to injectable GLP-1RAs. This article reviews data from: PIONEER 6, a phase 3a cardiovascular outcomes trial in patients at high cardiovascular risk; PIONEER 5, a phase 3a trial in patients with moderate renal impairment; a post-hoc analysis of PIONEER data by age; and pharmacokinetic trials investigating the effects of renal impairment, gastrointestinal disease, and hepatic impairment on the exposure of oral semaglutide. PIONEER 6 demonstrated the cardiovascular safety of oral semaglutide compared with placebo (hazard ratio: 0.79; 95% confidence interval [CI]: 0.57, 1.11; p < 0.001 for noninferiority), ruling out excess cardiovascular risk. In PIONEER 5, oral semaglutide was superior to placebo in decreasing glycated hemoglobin over 26 weeks (estimated treatment difference [ETD]: -0.8%; 95% CI: -1.0, -0.6; p < 0.0001) and body weight (ETD: -2.5 kg; 95% CI: -3.2, -1.8; p < 0.0001), and renal function was unchanged in both treatment groups. There was no effect of age on glycemic efficacy of oral semaglutide and the presence of upper gastrointestinal disease or hepatic impairment did not affect the pharmacokinetics of semaglutide. Across the trials, the safety profile of oral semaglutide was as expected for a GLP-1RA, with gastrointestinal adverse events most commonly reported. As such, oral semaglutide provides an effective oral GLP-1RA treatment option in older patients and/or those with comorbidities, with no requirements for dose adjustment.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Hipoglicemiantes/administração & dosagem , Fatores Etários , Idoso , Doenças Cardiovasculares/complicações , Comorbidade , Diabetes Mellitus Tipo 2/complicações , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Falência Renal Crônica/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
Postgrad Med ; 132(sup2): 48-60, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32815453

RESUMO

Oral semaglutide is the first US Food and Drug Administration-approved oral glucagon-like peptide-1 receptor agonist (GLP-1RA) for the treatment of type 2 diabetes (T2D). Prior articles within this supplement reviewed the PIONEER trial program, which demonstrated that oral semaglutide reduced glycated hemoglobin and body weight when given to patients with uncontrolled T2D on various background therapies, and had a safety profile consistent with subcutaneous GLP-1RAs. This article provides guidance on integrating oral semaglutide into clinical practice in primary care. Patient populations with T2D who may gain benefit from oral semaglutide include those with inadequate glycemic control taking one or more oral glucose-lowering medication (e.g. after metformin), patients for whom weight loss would be beneficial, patients at risk of hypoglycemia, those who would historically have been considered for treatment with a subcutaneous GLP-1RA, and those receiving basal insulin who require treatment intensification. Like other GLP-1RAs, oral semaglutide is contraindicated in those with personal/family history of medullary thyroid carcinoma, and in those with multiple endocrine neoplasia syndrome type 2, as noted in a boxed warning in the prescribing information. Oral semaglutide has not been studied in those with a history of pancreatitis, is not recommended in patients with suspected/confirmed pancreatitis, and is not indicated in type 1 diabetes. When initiating oral semaglutide, gradual dose escalation is recommended to minimize the risk of gastrointestinal adverse events. As food and excess liquid reduce oral semaglutide absorption, patients should swallow the tablet with up to 4 fl oz/120 mL of water on an empty stomach upon waking, and should wait at least 30 minutes before eating, drinking, or taking other oral medications. Those managing patients should be aware of the potential impact of these dosing conditions on concomitant medications. When counseling patients, it is important to discuss these administration instructions, realistic therapeutic expectations, and strategies for mitigation of gastrointestinal events. Oral semaglutide provides a new option for add-on to initial T2D therapy (or later in the treatment paradigm), with the potential to enable more patients to benefit from the improvements in glycemic control, reductions in body weight, and low risk of hypoglycemia afforded by GLP-1RAs.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Hipoglicemiantes/administração & dosagem , Atenção Primária à Saúde , Administração Oral , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos
7.
Nutr. hosp ; 37(3): 631-635, mayo-jun. 2020. graf
Artigo em Espanhol | IBECS | ID: ibc-193873

RESUMO

El fallo intestinal (FI) se define como una reducción de la función intestinal por debajo del mínimo necesario para la absorción de nutrientes y que precisa suplementación intravenosa para mantener la salud y/o el crecimiento. La causa más frecuente es el síndrome de intestino corto (SIC). Aproximadamente el 50 % de los pacientes con SIC presenta FI y requiere soporte parenteral. La teduglutida es un análogo del péptido-2 similar al glucagón (GLP-2) humano aprobado para el tratamiento de pacientes con SIC. Los resultados de ensayos clínicos han probado su eficacia: se reducen el volumen y los días de administración de nutrición parenteral y fluidoterapia. Pocas publicaciones evalúan los efectos sobre la función intestinal a largo plazo en pacientes respondedores tras la suspensión de teduglutida. Se describe un paciente con SIC tipo I (yeyunostomía terminal) debido a múltiples intervenciones quirúrgicas por enfermedad de Crohn, que recibió tratamiento con liraglutida un año y teduglutida secuencial durante 21 meses. Con el primero, se objetivó una reducción en la necesidad de aporte y débito por yeyunostomía. El análogo del GLP-2 consiguió una mayor reducción del desequilibrio hídrico que permitió suspender la sueroterapia nocturna, con ganancia ponderal y mantenimiento de parámetros nutricionales, situación mantenida dos años después de su suspensión


Intestinal failure (IF) is defined as a reduction in intestinal function below the minimum necessary for the absorption of nutrients, requiring intravenous supplementation to maintain health and/or growth. The most common cause is short bowel syndrome (SBS). Approximately 50 % of patients with SBS have IF and require parenteral support. Teduglutide is a human glucagon-like peptide-2 analogue (GLP-2) approved for the treatment of patients with SBS. Clinical trial results have proven its efficacy by reducing volume and days of administration of parenteral nutrition and fluid therapy. Few publications evaluate the effects on long-term bowel function in respondent patients after teduglutide suspension. A patient with type I SBS (terminal jejunostomy) due to multiple surgeries for Crohn's disease, who was treated with liraglutide for one year and sequential teduglutide for 21 months, is described. With the former, a reduction in the need for contribution and debit by jejunostomy was observed. The GLP-2 analogue achieved a greater reduction in the hydric disbalance that allowed the suspension of the nocturnal suerotherapy, with weight gain and maintenance of nutritional parameters; situation maintained two years after its suspension


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Nutrição Parenteral/métodos , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Síndrome do Intestino Curto/tratamento farmacológico , Nutrientes , Infusões Intravenosas/métodos , Hidratação , Valor Nutritivo
8.
Expert Opin Pharmacother ; 21(8): 953-967, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32237916

RESUMO

INTRODUCTION: There is an unmet medical need for an effective anti-fibrotic treatment for NASH with advanced fibrosis. AREAS COVERED: The authors review the current and novel agents for the treatment of NASH with fibrosis. They also consider the potential future strategies of combination therapies. EXPERT OPINION: Farnesoid X receptor (FXR) agonist (obeticholic acid [OCA]) significantly ameliorated hepatic fibrosis in NASH stage 2/3 fibrosis in an interim analysis of phase 3 trial. Because OCA has several drawbacks such as itching and elevated low-density lipoprotein-cholesterol (LDL-C), non-bile acid FXR agonists are now under development. Selonsertib (apoptosis signaling kinase 1 inhibitor), emricasan (an irreversible pan-caspase inhibitor), and simtsuzumab (a monoclonal antibody against lysyl oxidase-like 2) were discontinued because of no efficacy over placebo. Peroxisome proliferator-activator receptor α/δ agonists, C-C motif chemokine receptor-2/5 antagonists, and thyroid ß receptor agonist are ongoing in phase 3 trials. A variety of agents including fibroblast growth factor (FGF)-21 and FGF-19 agonists, as well as acetyl-CoA carboxylase inhibitors, are also expected. Among antidiabetic agents, semaglutide, a novel GLP-1 RA, is ongoing for NASH stage 1-3 fibrosis in a phase 2 trial. Furthermore, the combination of GLP-RA/glucagon receptor agonist and GLP-RA/gastrointestinal peptide agonist are promising future options.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pioglitazona/uso terapêutico , Vitamina E/uso terapêutico , Ácido Quenodesoxicólico/administração & dosagem , Ácido Quenodesoxicólico/uso terapêutico , Ensaios Clínicos como Assunto , Fatores de Crescimento de Fibroblastos/agonistas , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Pioglitazona/administração & dosagem , Receptores Citoplasmáticos e Nucleares/agonistas , Resultado do Tratamento , Vitamina E/administração & dosagem
9.
Value Health ; 23(4): 434-440, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32327160

RESUMO

OBJECTIVES: Outcomes-based contracts tie rebates and discounts for expensive drugs to outcomes. The objective was to estimate the utility of outcomes-based contracts for diabetes medications using real-world data and to identify methodologic limitations of this approach. METHODS: A population-based cohort study of adults newly prescribed a medication for diabetes with a publicly announced outcomes-based contract (ie, exenatide microspheres ["exenatide"], dulaglutide, or sitagliptin) was conducted. The comparison group included patients receiving canagliflozin or glipizide. The primary outcome was announced in the outcomes-based contract: the percentage of adults with a follow-up hemoglobin A1C <8% up to 1 year later. Secondary outcomes included the percentage of patients diagnosed with hypoglycemia and the cost of a 1-month supply. RESULTS: Thousands of adults newly filled prescriptions for exenatide (n = 5079), dulaglutide (n = 6966), sitagliptin (n = 40 752), canagliflozin (n = 16 404), or glipizide (n = 59 985). The percentage of adults subsequently achieving a hemoglobin A1C below 8% ranged from 83% (dulaglutide, sitagliptin) to 71% (canagliflozin). The rate of hypoglycemia was 25 per 1000 person-years for exenatide, 37 per 1000 person-years for dulaglutide, 28 per 1000 person-years for sitagliptin, 18 per 1000 person-years for canagliflozin, and 34 per 1000 person-years for glipizide. The cash price for a 1-month supply was $847 for exenatide, $859 for dulaglutide, $550 for sitagliptin, $608 for canagliflozin, and $14 for glipizide. CONCLUSION: Outcomes-based pricing of diabetes medications has the potential to lower the cost of medications, but using outcomes such as hemoglobin A1C may not be clinically meaningful because similar changes in A1C can be achieved with generic medications at a far lower cost.


Assuntos
Contratos/economia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Avaliação de Resultados em Cuidados de Saúde/métodos , Idoso , Canagliflozina/administração & dosagem , Canagliflozina/economia , Estudos de Coortes , Diabetes Mellitus Tipo 2/economia , Exenatida/administração & dosagem , Exenatida/economia , Feminino , Seguimentos , Glipizida/administração & dosagem , Glipizida/economia , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Peptídeos Semelhantes ao Glucagon/economia , Humanos , Hipoglicemiantes/economia , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/economia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/economia , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/economia
10.
Adv Ther ; 37(5): 2427-2441, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32306244

RESUMO

INTRODUCTION: Once-weekly semaglutide 1 mg is a novel glucagon-like peptide-1 receptor agonist (GLP-1 RA) for the treatment of type 2 diabetes that has demonstrated significantly greater reductions in glycated haemoglobin (HbA1c) and body weight than the GLP-1 RA once-daily liraglutide 1.2 mg in the SUSTAIN 10 trial. The present analysis aimed to evaluate the long-term cost-effectiveness of once-weekly semaglutide 1 mg versus once-daily liraglutide 1.2 mg from a UK healthcare payer perspective. METHODS: Long-term outcomes were projected using the IQVIA CORE Diabetes Model (version 9.0), with baseline characteristics and treatment effects sourced from SUSTAIN 10. Patients were assumed to initiate treatment with GLP-1 RAs and continue treatment until HbA1c exceeded 7.5%, at which point GLP-1 RAs were discontinued and basal insulin was initiated. Pharmacy costs and costs of complications were measured in 2018 pounds sterling (GBP), with future costs and outcomes discounted at 3.5% per annum. Utilities were taken from published sources. RESULTS: In the base-case analysis, once-weekly semaglutide 1 mg was associated with an increase in discounted life expectancy of 0.21 years and discounted quality-adjusted life expectancy of 0.30 quality-adjusted life-years, compared with once-daily liraglutide 1.2 mg. Clinical benefits were achieved at reduced costs, with lifetime cost savings of GBP 140 per patient with semaglutide versus liraglutide, owing to a reduction in diabetes-related complications, in particular cardiovascular disease (mean cost saving of GBP 279 per patient). Therefore, once-weekly semaglutide 1 mg was dominant compared with once-daily liraglutide 1.2 mg. The results of the sensitivity analyses were similar, demonstrating the robustness of the base-case analysis. CONCLUSIONS: Once-weekly semaglutide 1 mg is a cost-effective treatment option versus once-daily liraglutide 1.2 mg, based on the SUSTAIN 10 trial, from a UK healthcare payer perspective.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Idoso , Peso Corporal , Análise Custo-Benefício , Complicações do Diabetes/economia , Complicações do Diabetes/prevenção & controle , Esquema de Medicação , Feminino , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/economia , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/economia , Liraglutida/administração & dosagem , Liraglutida/economia , Masculino , Pessoa de Meia-Idade , Modelos Econométricos , Anos de Vida Ajustados por Qualidade de Vida , Reino Unido
11.
Metabolism ; 106: 154190, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32109448

RESUMO

INTRODUCTION AND AIM: Real-word data on the head-to-head comparisons among glucagon-like peptide-1 receptor agonists (GLP-1RA) are scant. Therefore, we aimed to compare the effectiveness of dulaglutide versus liraglutide and exenatide once weekly (exeOW) in type 2 diabetic (T2D) patients under routine care. METHODS: This was a retrospective, multicenter, real-world study on patients with T2D (aged 18-80) initiating a GLP-1RA between 2010 and 2018 at specialist outpatient clinics. We compared the effectiveness of dulaglutide versus liraglutide and exeOW on the changes in HbA1c (primary outcome), body weight, blood pressure and fasting glucose (secondary outcomes). Average follow-up was 5.9 months. Channelling biases were addressed with propensity score matching or multivariable adjustment. Meta-analyses of observational studies, covering the same comparisons, are also presented. RESULTS: 849, 1371 and 198 patients were included in the dulaglutide, liraglutide and exeOW groups, respectively. The reduction of HbA1c was greater with dulaglutide than with liraglutide (-0.24 ±â€¯0.08%; p = 0.003), and was confirmed in the meta-analysis of observational studies. In our study, dulaglutide showed similar effectiveness compared to exeOW. When these results were pooled with other observational studies, dulaglutide showed a greater reduction of HbA1c (-0.19%; p = 0.003) and body weight (-0.8 kg; p = 0.007). CONCLUSIONS: In a real-world scenario, dulaglutide reduced HbA1c more than liraglutide. Conversely, we found similar effect of dulaglutide and exeOW, with statistical differences arising solely when results were meta-analysed with those from other observational studies. Lack of up-titration for liraglutide and higher discontinuation rate for exeOW likely influenced the estimated treatment difference.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida/administração & dosagem , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Liraglutida/administração & dosagem , Estudos Observacionais como Assunto/estatística & dados numéricos , Proteínas Recombinantes de Fusão/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Esquema de Medicação , Quimioterapia Combinada , Exenatida/efeitos adversos , Feminino , Seguimentos , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Liraglutida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
12.
Drugs ; 80(2): 197-208, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32002850

RESUMO

Subcutaneous dulaglutide (Trulicity®) is a once-weekly glucagon-like peptide-1 receptor agonist that is approved in numerous countries as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes (T2D). In the clinical trial and real-world settings, once-weekly subcutaneous dulaglutide, as monotherapy or add-on therapy to other antihyperglycaemic agents (including oral antihyperglycaemic drugs and insulin), was an effective and generally well tolerated treatment in adults with inadequately controlled T2D, including in high-risk patients [e.g. obese and elderly patients, those with stage 3 or 4 chronic kidney disease (CKD) and/or cardiovascular (CV) disease]. In the REWIND CV outcomes trial in patients with T2D with or without CV disease, dulaglutide was associated with a significant reduction in the risk of a major adverse cardiac event (MACE; primary composite outcome comprising CV death, nonfatal myocardial infarction or nonfatal stroke) at a median of 5.4 years' follow-up. Given its durable glycaemic efficacy, beneficial effects on bodyweight and MACE outcomes, low inherent risk of hypoglycaemia and convenient once-weekly regimen, dulaglutide remains an important option in the management of T2D.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/administração & dosagem , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Injeções Subcutâneas , Proteínas Recombinantes de Fusão/administração & dosagem
13.
Adv Ther ; 37(3): 1248-1259, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32048148

RESUMO

INTRODUCTION: Once-weekly semaglutide 1 mg is a novel glucagon-like peptide 1 receptor agonist (GLP-1 RA) that, in the SUSTAIN clinical trials, has demonstrated greater reductions in glycated haemoglobin (HbA1c) and body weight than the other GLP-1 RAs exenatide extended-release (ER) 2 mg, dulaglutide 1.5 mg and liraglutide 1.2 mg. The aim of this analysis was to evaluate the relative cost of control of achieving treatment goals in people with type 2 diabetes (T2D) treated with once-weekly semaglutide versus exenatide ER, dulaglutide and liraglutide from a UK perspective. METHODS: Proportions of patients reaching HbA1c targets (< 7.0% and < 7.5%), weight loss targets (≥ 5% reduction in body weight) and composite endpoints (HbA1c < 7.0% without weight gain or hypoglycaemia; reduction in HbA1c of ≥ 1% and weight loss of ≥ 5%) were obtained from the SUSTAIN clinical trials. Annual per patient treatment costs were based on wholesale acquisition costs from July 2019 in the UK. Cost of control was calculated by plotting relative treatment costs against relative efficacy. RESULTS: The annual per patient cost was similar for all GLP-1 RAs. Once-weekly semaglutide was superior to exenatide ER, dulaglutide and liraglutide in bringing patients to HbA1c and weight loss targets, and to composite endpoints. When looking at the composite endpoint of HbA1c < 7.0% without weight gain or hypoglycaemia, exenatide ER, dulaglutide and liraglutide were 50.0%, 21.6% and 51.3% less efficacious in achieving this, respectively, than once-weekly semaglutide. Consequently, the efficacy-to-cost ratios for once-weekly semaglutide were superior to all comparators in bringing patients to all endpoints. CONCLUSIONS: The present study showed that once-weekly semaglutide offers superior cost of control versus exenatide ER, dulaglutide and liraglutide in terms of achieving clinically relevant, single and composite endpoints. Once-weekly semaglutide 1 mg would therefore represent good value for money in the UK setting.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/economia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Hipoglicemiantes/economia , Hipoglicemiantes/uso terapêutico , Peso Corporal , Análise Custo-Benefício , Esquema de Medicação , Exenatida/economia , Exenatida/uso terapêutico , Feminino , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hemoglobina A Glicada/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/administração & dosagem , Fragmentos Fc das Imunoglobulinas/economia , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Liraglutida/economia , Liraglutida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/economia , Proteínas Recombinantes de Fusão/uso terapêutico , Reino Unido , Ganho de Peso
15.
Drug Des Devel Ther ; 13: 2985-2996, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686781

RESUMO

Glucagon-like peptide 1 receptor agonists (GLP1-RA) are prominent agents in the therapeutics of type 2 diabetes mellitus due to their exemplary efficacy in both preprandial and postprandial glycemia, their safety, low risk of hypoglycemia, their multilevel pathophysiological superiority, weight loss and importantly the observed benefits in cardiovascular disease reduction. Their major drawback is the subcutaneous route of administration, constituting a barrier to adoption and reason for treatment discontinuation. Thus, the development of an oral GLP1-RA agent would promote medication adherence and quality of life, further consolidating its beneficial effects in real-life clinical practice. However, this task is hampered by suboptimal gastrointestinal protein absorption. Yet, the introduction of oral semaglutide, a modified form of semaglutide with the addition of a carrier sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, may have provided a safe and effective way to reach systemic circulation while other molecules are in development. Whether this molecule still has the impressive cardiovascular effects demonstrated with the use of its precursor remains to be explored. However, to date, its efficacy and safety have already been showcased in a randomized trial. More research is warranted in order to further consolidate these findings across different type 2 diabetes mellitus (T2DM) subpopulations, and adequately powered studies with a longer follow-up that would allow the exploration of microvascular and macrovascular complications are needed. Finally, studies comparing oral semaglutide and similar molecules with other currently established antidiabetic agents to evaluate the relative efficacy, the cost-effectiveness and further understand its place in T2DM therapeutic algorithm are needed. This review focuses on the development of oral GLP1-RA agents and summarizes the challenges, milestones and expected benefits associated with a successful introduction.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/farmacologia , Hipoglicemiantes/farmacologia , Administração Oral , Diabetes Mellitus Tipo 2/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/química , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química
16.
Endocr Regul ; 53(3): 187-190, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517629

RESUMO

OBJECTIVE: While dulaglutide has been approved inpatients with type 2 diabetes (T2DM) in combination with insulin, it has not been studied in insulin-deficient patients, not whether they have type 1 diabetes (T1DM) or T2DM. The aim of this study is to assess the efficacy and safety of dulaglutide 0.75 mg/once weekly (QW) in patients with absolute insulin deficiency (n=10). SUBJECTS AND RESULTS: Significant reductions of HbA1c (9.30±1.03% to 8.61±1.21%; p<0.02) and body mass index (BMI; 23.61±3.95 to 23.41±4.24; p<0.02) levels were observed at 3 months with the addition of dulaglutide to the existing pharmacotherapy. However, in all the patients, post-meal C-peptide levels remained undetectable. One patient had gastrointestinal adverse events and discontinue dulaglutide within the first month. One patient was a non-responder, who had little if any changes in HbA1c levels at 3 months. CONCLUSIONS: The results indicate that dulaglutide is effective in patients with T1DM or T2DM with absolute insulin deficiency, though gastrointestinal adverse events might be of concern. The improvements in glycemic control could not be due to enhanced insulin secretion, but may be as a result of a combination of the other effects of glucagon like peptide 1 (GLP-1), such as postprandial glucagon suppression, delayed gastric emptying, and weight loss.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Insulina/deficiência , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Idoso , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Esquema de Medicação , Quimioterapia Combinada , Feminino , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Hemoglobina A Glicada/análise , Hemoglobina A Glicada/efeitos dos fármacos , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
17.
Cardiovasc Diabetol ; 18(1): 73, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31167654

RESUMO

BACKGROUND: The SUSTAIN 6 trial demonstrated that once-weekly semaglutide (0.5 and 1.0 mg) significantly reduced major adverse cardiovascular (CV) events (MACE) vs placebo in subjects with type 2 diabetes (T2D) and high CV risk. The effects of gender, age and baseline CV risk on outcomes are important considerations for further study. METHODS: Subjects were grouped according to gender, age (50-65 years and > 65 years), and CV risk profile at baseline (prior myocardial infarction [MI] or stroke vs no prior MI or stroke, and established CV disease [CVD] vs CV risk factors alone, including subjects with chronic kidney disease). Time to MACE and its individual components (CV death, nonfatal MI, nonfatal stroke), hospitalization for unstable angina or heart failure, and revascularization (coronary and peripheral) were analyzed for all subgroups. Additional analyses were performed for gender and age to investigate change from baseline in HbA1c and body weight, as well as tolerability. RESULTS: A total of 3297 subjects were included. The majority of subjects (60.7%) were male; 43% were > 65 years of age; 41.5% had a history of MI or stroke; and 76.8% had established CVD. Compared with placebo, semaglutide reduced the risk of the first occurrence of MACE and each MACE component consistently across all subgroups (gender, age, and baseline CV risk profile). Revascularizations, HbA1c and body weight were also reduced consistently across all subgroups compared with placebo. Gastrointestinal adverse events in all treatment groups were more common among women than men, but rates of premature treatment discontinuation were similar for both genders. CONCLUSIONS: In this post hoc analysis of SUSTAIN 6, once-weekly semaglutide vs placebo reduced the risk of MACE in all subjects included in the trial, regardless of gender, age, or baseline CV risk profile. Trial registry Clinicaltrials.gov, Identifying number: NCT01720446, Date of registration: October 29, 2012.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Hipoglicemiantes/administração & dosagem , Incretinas/administração & dosagem , Fatores Etários , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Ensaios Clínicos Fase III como Assunto , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Esquema de Medicação , Feminino , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Humanos , Hipoglicemiantes/efeitos adversos , Incretinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Proteção , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Fatores Sexuais , Fatores de Tempo , Resultado do Tratamento
18.
J Diabetes Res ; 2019: 6423987, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183384

RESUMO

Objective: To evaluate the effects of once-weekly dulaglutide injection and once-daily glimepiride on glucose fluctuation in patients with type 2 diabetes mellitus (T2DM) using the Continuous Glucose Monitoring System (CGMS). Methods: A total of 23 patients with T2DM were randomly assigned into two groups for 26 weeks: the dulaglutide group (n = 13) and the glimepiride group (n = 10). 72-hour CGMS was applied to all patients: before and after the treatment. General clinical data were collected and measured, such as fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), tumor necrosis factor-α (TNF-α), 8-iso-prostaglandin F2α (8-iso-PGF2α), and interleukin-6 (IL-6). Results: HbA1c of the dulaglutide group was reduced from 8.38 ± 0.93% to 6.68 ± 0.73% after the treatment (P < 0.05); similarly, it was reduced from 7.91 ± 0.98% to 6.67 ± 0.74% (P < 0.05) in the glimepiride group. The levels of serum 8-iso-PGF2α, TNF-α, and IL-6 all decreased significantly in both groups after treatment, and there was no significant difference found between the two groups (P > 0.05). The Mean Blood Glucose (MBG) of the two groups declined significantly after therapy (P < 0.05). However, the Standard Deviation of Blood Glucose (SDBG) decreased significantly only in the dulaglutide group (from 2.57 ± 0.74 mmol/L to 1.98 ± 0.74 mmol/L, P < 0.05). There were no significant changes of Mean Amplitude of Glycemic Excursion (MAGE) and Absolute Means of Daily Difference (MODD) after treatment in both groups. Furthermore, no statistically significant difference was found between the two groups in MBG, SDBG, MAGE, and MODD (P > 0.05). The percentage time (PT) (>10 mmol/L and 3.9-10 mmol/L) of the two groups was significantly changed after the treatment (P < 0.05). However, this was not seen in the PT < 3.9 mmol/L after the treatment (P > 0.05). Conclusion: Once-weekly dulaglutide injection has the same effectiveness as daily glimepiride on lowering blood glucose and decreasing oxidation stress and inflammation and is more effective in controlling glucose fluctuation as compared with glimepiride. This trial is registered with ClinicalTrials.gov NCT01644500.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Esquema de Medicação , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/administração & dosagem , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Compostos de Sulfonilureia/administração & dosagem , Automonitorização da Glicemia , Dinoprosta/análogos & derivados , Dinoprosta/metabolismo , Feminino , Seguimentos , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Hemoglobina A Glicada/metabolismo , Humanos , Inflamação , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Monitorização Ambulatorial , Estresse Oxidativo , Fator de Necrose Tumoral alfa/metabolismo
19.
N Engl J Med ; 381(9): 841-851, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31185157

RESUMO

BACKGROUND: Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide. METHODS: We assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors only). The primary outcome in a time-to-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome). RESULTS: A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease. The median time in the trial was 15.9 months. Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority). Results for components of the primary outcome were as follows: death from cardiovascular causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (hazard ratio, 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (hazard ratio, 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), respectively (hazard ratio, 0.74; 95% CI, 0.35 to 1.57). Death from any cause occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 (2.8%) in the placebo group (hazard ratio, 0.51; 95% CI, 0.31 to 0.84). Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide. CONCLUSIONS: In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo. (Funded by Novo Nordisk; PIONEER 6 ClinicalTrials.gov number, NCT02692716.).


Assuntos
Doenças Cardiovasculares/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Hipoglicemiantes/administração & dosagem , Administração Oral , Idoso , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Risco
20.
Lancet ; 394(10192): 39-50, 2019 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-31186120

RESUMO

BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists are effective treatments for type 2 diabetes, lowering glycated haemoglobin (HbA1c) and weight, but are currently only approved for use as subcutaneous injections. Oral semaglutide, a novel GLP-1 agonist, was compared with subcutaneous liraglutide and placebo in patients with type 2 diabetes. METHODS: In this randomised, double-blind, double-dummy, phase 3a trial, we recruited patients with type 2 diabetes from 100 sites in 12 countries. Eligible patients were aged 18 years or older, with HbA1c of 7·0-9·5% (53-80·3 mmol/mol), on a stable dose of metformin (≥1500 mg or maximum tolerated) with or without a sodium-glucose co-transporter-2 inhibitor. Participants were randomly assigned (2:2:1) with an interactive web-response system and stratified by background glucose-lowering medication and country of origin, to once-daily oral semaglutide (dose escalated to 14 mg), once-daily subcutaneous liraglutide (dose escalated to 1·8 mg), or placebo for 52 weeks. Two estimands were defined: treatment policy (regardless of study drug discontinuation or rescue medication) and trial product (assumed all participants were on study drug without rescue medication) in all participants who were randomly assigned. The treatment policy estimand was the primary estimand. The primary endpoint was change from baseline to week 26 in HbA1c (oral semaglutide superiority vs placebo and non-inferiority [margin: 0·4%] and superiority vs subcutaneous liraglutide) and the confirmatory secondary endpoint was change from baseline to week 26 in bodyweight (oral semaglutide superiority vs placebo and liraglutide). Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on Clinicaltrials.gov, number NCT02863419, and the European Clinical Trials registry, number EudraCT 2015-005210-30. FINDINGS: Between Aug 10, 2016, and Feb 7, 2017, 950 patients were screened, of whom 711 were eligible and randomly assigned to oral semaglutide (n=285), subcutaneous liraglutide (n=284), or placebo (n=142). 341 (48%) of 711 participants were female and the mean age was 56 years (SD 10). All participants were given at least one dose of study drug, and 277 (97%) participants in the oral semaglutide group, 274 (96%) in the liraglutide group, and 134 (94%) in the placebo group completed the 52-week trial period. Mean change from baseline in HbA1c at week 26 was -1·2% (SE 0·1) with oral semaglutide, -1·1% (SE 0·1) with subcutaneous liraglutide, and -0·2% (SE 0·1) with placebo. Oral semaglutide was non-inferior to subcutaneous liraglutide in decreasing HbA1c (estimated treatment difference [ETD] -0·1%, 95% CI -0·3 to 0·0; p<0·0001) and superior to placebo (ETD -1·1%, -1·2 to -0·9; p<0·0001) by use of the treatment policy estimand. By use of the trial product estimand, oral semaglutide had significantly greater decreases in HbA1c than both subcutaneous liraglutide (ETD -0·2%, 95% CI -0·3 to -0·1; p=0·0056) and placebo (ETD -1·2%, -1·4 to -1·0; p<0·0001) at week 26. Oral semaglutide resulted in superior weight loss (-4·4 kg [SE 0·2]) compared with liraglutide (-3·1 kg [SE 0·2]; ETD -1·2 kg, 95% CI -1·9 to -0·6; p=0·0003) and placebo (-0·5 kg [SE 0·3]; ETD -3·8 kg, -4·7 to -3·0; p<0·0001) at week 26 (treatment policy). By use of the trial product estimand, weight loss at week 26 was significantly greater with oral semaglutide than with subcutaneous liraglutide (-1·5 kg, 95% CI -2·2 to -0·9; p<0·0001) and placebo (ETD -4·0 kg, -4·8 to -3·2; p<0·0001). Adverse events were more frequent with oral semaglutide (n=229 [80%]) and subcutaneous liraglutide (n=211 [74%]) than with placebo (n=95 [67%]). INTERPRETATION: Oral semaglutide was non-inferior to subcutaneous liraglutide and superior to placebo in decreasing HbA1c, and superior in decreasing bodyweight compared with both liraglutide and placebo at week 26. Safety and tolerability of oral semaglutide were similar to subcutaneous liraglutide. Use of oral semaglutide could potentially lead to earlier initiation of GLP-1 receptor agonist therapy in the diabetes treatment continuum of care. FUNDING: Novo Nordisk A/S.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Liraglutida/administração & dosagem , Metformina/administração & dosagem , Administração Oral , Idoso , Peso Corporal/efeitos dos fármacos , Método Duplo-Cego , Feminino , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Injeções Subcutâneas , Liraglutida/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Resultado do Tratamento
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